Azetidine, pyrrolidine and piperidine derivatives as 5HT1 receptor agonists

ABSTRACT

A class of substituted azetidine, pyrrolidine and piperidine derivatives are selective agonists of 5-HT 1  -like receptors, being potent agonists of the human 5-HT 1D α  receptor subtype whilst possessing at least a 10-fold selective affinity for the 5-HT 1D α  receptor subtype relative to the 5-HT 1D β subtype; they are therefore useful in the treatment and/or prevention of clinical conditions, in particular migraine and associated disorders, for which a subtype-selective agonist of 5-HT 1D  receptors is indicated, whilst eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT 1D  receptor agonists.

The present invention relates to a class of substituted azetidine,pyrrolidine and piperidine derivatives which act on 5-hydroxytryptamine(5-HT) receptors, being selective agonists of so-called "5-HT₁ -like"receptors. They are therefore useful in the treatment of clinicalconditions for which a selective agonist of these receptors isindicated.

It has been known for some time that 5-HT₁ -like receptor agonists whichexhibit selective vasoconstrictor activity are of use in the treatmentof migraine (see, for example, A. Doenicke et al., The Lancet, 1988,Vol. 1, 1309-11; and W. Feniuk and P. P. A. Humphrey, Drug DevelopmentResearch, 1992, 26, 235-240).

The human 5-HT₁ -like or 5-HT_(1D) receptor has recently been shown bymolecular cloning techniques to exist in two distinct subtypes. Thesesubtypes have been termed 5-HT_(1D)α (or 5-HT_(1D-1)) and 5-HT_(1D)β (or5-HT_(1D-2)), and their amino acid sequences are disclosed and claimedin WO-A-91/17174.

The 5-HT_(1D)α receptor subtype in humans is believed to reside onsensory terminals in the dura mater. Stimulation of the 5-HT_(1D)αsubtype inhibits the release of inflammatory neuropeptides which arethought to contribute to the headache pain of migraine. The human5-HT_(1D)β receptor subtype, meanwhile, is located predominantly on theblood vessels and in the brain, and hence may play a part in mediatingconstriction of cerebral and coronary arteries, as well as CNS effects.

Administration of the prototypical 5-HT_(1D) agonist sumatriptan(GR43175) to humans is known to give rise at therapeutic doses tocertain adverse cardiovascular events (see, for example, F. Willett etal., Br. Med. J., 1992, 304, 1415; J. P. Ottervanger et al., The Lancet,1993, 341, 861-2; and D. N. Bateman, The Lancet, 1993, 341, 221-4).Since sumatriptan barely discriminates between the human 5-HT_(1D)α and5-HT_(1D)β receptor subtypes (cf. WO-A-91/17174, Table 1), and since itis the blood vessels with which the 5-HT_(1D)β subtype is most closelyassociated, it is believed that the cardiovascular side-effects observedwith sumatriptan can be attributed to stimulation of the 5-HT_(1D)βreceptor subtype. It is accordingly considered (cf. G. W. Rebeck et al.,Proc. Natl. Acad. Sci. USA, 1994, 91, 3666-9) that compounds which caninteract selectively with the 5-HT_(1D)α receptor subtype, whilst havinga less pronounced action at the 5-HT_(1D)β subtype, might be free from,or at any rate less prone to, the undesirable cardiovascular and otherside-effects associated with non-subtype-selective 5-HT_(1D) receptoragonists, whilst at the same time maintaining a beneficial level ofanti-migraine activity.

The compounds of the present invention, being selective 5-HT₁ -likereceptor agonists, are accordingly of benefit in the treatment ofmigraine and associated conditions, e.g. cluster headache, chronicparoxysmal hemicrania, headache associated with vascular disorders,tension headache and paediatric migraine. In particular, the compoundsaccording to this invention are potent agonists of the human 5-HT_(1D)αreceptor subtype. Moreover, the compounds in accordance with thisinvention have been found to possess at least a 10-fold selectiveaffinity for the 5-HT_(1D)α receptor subtype relative to the 5-HT_(1D)βsubtype, and they can therefore be expected to manifest fewerside-effects than those associated with non-subtype-selective 5-HT_(1D)receptor agonists.

Several distinct classes of heteroaromatic compounds based on inter aliaa substituted tryptamine ring system are described in publishedInternational patent applications 91/18897, 94/02460 and 94/02477. Thecompounds described therein are stated to be agonists of 5-HT₁ -likereceptors, and accordingly to be of particular use in the treatment ofmigraine and associated conditions. None of these publications, however,discloses or even suggests the substituted azetidine, pyrrolidine andpiperidine derivatives provided by the present invention.

In EP-A-0548813 is described a series of alkoxypyridin-4-yl andalkoxypyrimidin-4-yl derivatives of indol-3-ylalkylpiperazines which arealleged to provide treatment of vascular or vascular-related headaches,including migraine. There is, however, no disclosure nor any suggestionin EP-A-0548813 of replacing the precisely substituted piperazine moietydescribed therein with a substituted azetidine, pyrrolidine orpiperidine moiety.

Moreover, nowhere in the prior art available to date is there anydisclosure of a subtype-selective 5-HT_(1D) receptor agonist having a5-HT_(1D)α receptor binding affinity (IC₅₀) below 50 nM and at least a10-fold selective affinity for the 5-HT_(1D)α receptor subtype relativeto the 5-HT_(1D)β subtype.

The compounds according to the present invention are subtype-selective5-HT_(1D) receptor agonists having a human 5-HT_(1D)α receptor bindingaffinity (IC₅₀) below 50 nM, typically below 10 nM and preferably below1 nM; and at least a 10-fold selective affinity, typically at least a50-fold selective affinity and preferably at least a 100-fold selectiveaffinity, for the human 5-HT_(1D)α receptor subtype relative to the5-HT_(1D)β subtype.

The present invention provides a compound of formula I, or a salt orprodrug thereof: ##STR1## wherein Z represents hydrogen, halogen, cyano,nitro, trifluoromethyl, --OR⁵, --OCOR⁵, --OCONR⁵ R⁶, --OCH₂ CN, --OCH₂CONR⁵ R⁶, --SR⁵, --SOR⁵, --SO₂ R⁵, --SO₂ NR⁵ R⁶, --NR⁵ R⁶, --NR⁵ COR⁶,--NR⁵ CO₂ R⁶, --NR⁵ SO₂ R⁶, --COR⁵, --CO₂ R⁵, --CONR⁵ R⁶, or a group offormula (a), (b), (c) or (d): ##STR2## in which the asterisk * denotes achiral centre; X represents oxygen, sulphur, --NH-- or methylene;

Y represents oxygen or sulphur;

E represents a chemical bond or a straight or branched alkylene chaincontaining from 1 to 4 carbon atoms;

Q represents a straight or branched alkylene chain containing from 1 to4 carbon atoms, optionally substituted in any position by a hydroxygroup;

U represents nitrogen or C--R² ;

V represents oxygen, sulphur or N--R³ ;

R², R³ and R⁴ independently represent hydrogen or C₁₋₆ alkyl;

R⁵ and R⁶ independently represent hydrogen, C₁₋₆ alkyl, trifluoromethyl,phenyl, methylphenyl, or an optionally substituted aryl(C₁₋₆)alkyl orheteroaryl(C₁₋₆)alkyl group; or R⁵ and R⁶, when linked through anitrogen atom, together represent the residue of an optionallysubstituted azetidine, pyrrolidine, piperidine, morpholine or piperazinering;

M represents the residue of an azetidine, pyrrolidine or piperidinering;

R represents a group of formula --W--R¹ ;

W represents a chemical bond or a straight or branched alkylene chaincontaining from 1 to 4 carbon atoms;

R¹ represents --OR^(x), --SR^(x) or --NR^(x) R^(y) ;

R^(x) and R^(y) independently represent hydrogen, hydrocarbon or aheterocyclic group, or R^(x) and R^(y) together represent a C₂₋₆alkylene group; and

R^(a) represents hydrogen, hydroxy, hydrocarbon or a heterocyclic group.

The present invention also provides compounds of formula I above, andsalts and prodrugs thereof, wherein R⁵ and R⁶ independently representhydrogen, C₁₋₆ alkyl, trifluoromethyl, methylphenyl, or an optionallysubstituted aryl(C₁₋₆)alkyl or heteroaryl(C₁₋₆)alkyl group.

When R⁵ and R⁶, when linked through a nitrogen atom, together representthe residue of an azetidine, pyrrolidine, piperidine, morpholine orpiperazine ring, this ring may be unsubstituted or substituted by one ormore substituents. Examples of suitable substituents include C₁₋₆ alkyl,aryl(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₂₋₆ alkoxycarbonyl and C₁₋₆alkylaminocarbonyl. Typical substituents include methyl, benzyl,methoxy, methoxycarbonyl, ethoxycarbonyl and methylaminocarbonyl. Inparticular, where R⁵ and R⁶ together represent the residue of apiperazine ring, this ring is preferably substituted on the distalnitrogen atom by a C₂₋₆ alkoxycarbonyl moiety such as methoxycarbonyl orethoxycarbonyl.

For use in medicine, the salts of the compounds of formula I will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts; alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic ligands, e.g. quaternaryammonium salts.

The term "hydrocarbon" as used herein includes straight-chained,branched and cyclic groups containing up to 18 carbon atoms, suitably upto 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitablehydrocarbon groups include C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl and aryl(C₁₋₆)alkyl.

The expression "a heterocyclic group" as used herein includes cyclicgroups containing up to 18 carbon atoms and at least one heteroatompreferably selected from oxygen, nitrogen and sulphur. The heterocyclicgroup suitably contains up to 15 carbon atoms and conveniently up to 12carbon atoms, and is preferably linked through carbon. Examples ofsuitable heterocyclic groups include C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl and heteroaryl(C₁₋₆)alkylgroups.

Suitable alkyl groups include straight-chained and branched alkyl groupscontaining from 1 to 6 carbon atoms. Typical examples include methyl andethyl groups, and straight-chained or branched propyl and butyl groups.Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl andt-butyl.

Suitable alkenyl groups include straight-chained and branched alkenylgroups containing from 2 to 6 carbon atoms. Typical examples includevinyl and allyl groups.

Suitable alkynyl groups include straight-chained and branched alkynylgroups containing from 2 to 6 carbon atoms. Typical examples includeethynyl and propargyl groups.

Suitable cycloalkyl groups include groups containing from 3 to 7 carbonatoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.

Particular aryl groups include phenyl and naphthyl.

Particular aryl(C₁₋₆)alkyl groups include benzyl, phenylethyl,phenylpropyl and naphthylmethyl.

Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl and morpholinyl groups.

Suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl,dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl,indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,benzidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolylgroups.

The expression "heteroaryl(C₁₋₆)alkyl" as used herein includesfurylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl,oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl,imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl,thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl,tetrazolylmethyl, tetrazolylethyl, pyridylmethyl, pyridylethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolylmethyl andisoquinolylmethyl.

The hydrocarbon and heterocyclic groups, as well as the aryl(C₁₋₆)alkylor heteroaryl(C₁₋₆)alkyl groups R⁵ and/or R⁶, may in turn be optionallysubstituted by one or more groups selected from C₁₋₆ alkyl, adamantyl,phenyl, halogen, C₁₋₆ haloalkyl, C₁₋₃ aminoalkyl, trifluoromethyl,hydroxy, C₁₋₆ alkoxy, aryloxy, keto, C₁₋₃ alkylenedioxy, nitro, cyano,carboxy, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, C₂₋₆alkylcarbonyloxy, arylcarbonyloxy, C₂₋₆ alkylcarbonyl, arylcarbonyl,C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl, arylsulphonyl,--NR^(v) R^(w), --NR^(v) COR^(w), --NR^(v) CO₂ R^(w), --NR^(v) SO₂R^(w), --CH₂ NR^(v) SO₂ R^(w), --NHCONR^(v) R^(w), --CONR^(v) R^(w),--SO₂ NR^(v) R^(w) and --CH₂ SO₂ NR^(v) R^(w), in which R^(v) and R^(w)independently represent hydrogen, C₁₋₆ alkyl, aryl or aryl(C₁₋₆)alkyl,or R^(v) and R^(w), together represent a C₂₋₆ alkylene group.

When R^(x) and R^(y), or R^(v) and R^(w), together represent a C₂₋₆alkylene group, this group may be an ethylene, propylene, butylene,pentamethylene or hexamethylene group, preferably butylene orpentamethylene.

The term "halogen" as used herein includes fluorine, chlorine, bromineand iodine, especially fluorine.

The present invention includes within its scope prodrugs of thecompounds of formula I above. In general, such prodrugs will befunctional derivatives of the compounds of formula I which are readilyconvertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Forexample, the compounds of formula I above wherein Z represents a groupof formula (b) or (c) have a chiral centre denoted by the asterisk *,which may accordingly be in the (R) or (S) configuration. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

In particular, where M represents the residue of a pyrrolidine ring, andthe substituent R is attached to the 2-position thereof, then theabsolute stereochemical configuration of the carbon atom at the point ofattachment of the moiety R is preferably as depicted in structure IA asfollows: ##STR3## wherein Z, E, Q, U, V, R and R^(a) are as definedabove.

Moreover, where M represents the residue of a pyrrolidine ring, and thesubstituent R is attached to the 3-position thereof, then the absolutestereochemical configuration of the carbon atom at the point ofattachment of the moiety R is preferably as depicted in structure IB asfollows: ##STR4## wherein Z, E, Q, U, V, R and R^(a) are as definedabove.

Where E, Q and W, which may be the same or different, represent straightor branched alkylene chains, these may be, for example, methylene,ethylene, 1-methylethylene, propylene, 2-methylpropylene or butylene. Inaddition, the alkylene chain Q may be substituted in any position by ahydroxy group giving rise, for example, to a 2-hydroxypropylene or2-hydroxymethyl-propylene chain Q. Moreover, E and W may eachindependently represent a chemical bond. Where E represents a chemicalbond, the moiety Z is attached directly to the benzo moiety of thecentral fused bicyclic heteroaromatic ring system. Similarly, where Wrepresents a chemical bond, the substituent R¹ is attached directly tothe azetidine, pyrrolidine or piperidine ring of which M is the residue.

Suitably, E represents a chemical bond or a methylene linkage.

Suitably, Q represents an ethylene or propylene linkage.

The compound of formula I in accordance with the present invention issuitably an indole, benzofuran or benzthiophene derivative of formulaIC, or an indazole derivative of formula ID: ##STR5## wherein Z, E, Q,V, M, R, R^(a), R² and R³ are as defined above. Preferably, thecompounds according to the invention are indole derivatives of formulaIE: ##STR6## wherein Z, E, Q, M, R, R^(a), R² and R³ are as definedabove, in particular wherein R² and R³ are both hydrogen.

Suitably, W represents a chemical bond or a methylene linkage.

Suitably, R^(x) and R^(y) independently represent hydrogen, C₁₋₆ alkyl,aryl, aryl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any of whichgroups may be optionally substituted by one or more substituentsselected typically from halogen, hydroxy, C₁₋₆ alkoxy, amino, C₂₋₆alkylcarbonylamino, C₁₋₆ alkylsulphonylamino and C₁₋₆alkylaminosulphonylmethyl. Particular values of R^(x) and R^(y) includehydrogen, methyl, benzyl, fluorobenzyl, methoxy-benzyl,acetylaminobenzyl, 1-phenylethyl, 2-phenylethyl,2-hydroxy-1-phenylethyl, 1-(acetylamino-phenyl)ethyl,2-(acetylamino-phenyl)ethyl, 1-hydroxy-3-phenylprop-2-yl,1-hydroxy-1-phenylprop-2-yl, furylmethyl, thienylmethyl andpyridylmethyl.

Suitable values for the substituent R¹ include hydroxy, benzyloxy,methoxy-benzyloxy, pyridylmethoxy, amino, methylamino, benzylamino,N-(acetylamino-benzyl)-amino, N-(1-phenylethyl)-amino,N-(2-phenylethyl)-amino, N-(2-hydroxy-1-phenylethyl)-amino,N-[1-(acetylamino-phenyl)ethyl]-amino,N-[2-(acetylamino-phenyl)ethyl]-amino,N-(1-hydroxy-3-phenylprop-2-yl)-amino,N-(1-hydroxy-1-phenylprop-2-yl)-amino, N-(furylmethyl)-amino,N-(pyridylmethyl)-amino, dimethylamino, N-benzyl-N-methylamino,N-fluorobenzyl-N-methylamino, N-(acetylamino-benzyl)-N-methylamino,N-methyl-N-(1-phenylethyl)-amino,N-(2-hydroxy-1-phenylethyl)-N-methylamino,N-[2-(acetylamino-phenyl)ethyl]-N-methylamino andN-methyl-N-(thienylmethyl)-amino.

Particular values of the group R include hydroxy, benzyloxy,benzyloxymethyl, methoxy-benzyloxy, pyridylmethoxy, benzylamino,benzylaminomethyl, N-(acetylamino-benzyl)-amino,N-(acetylamino-benzyl)-aminomethyl, N-(1-phenylethyl)-amino,N-(1-phenylethyl)-aminomethyl, N-(2-hydroxy-1-phenylethyl)-amino,N-(2-hydroxy-1-phenylethyl)-aminomethyl,N-[1-(acetylamino-phenyl)ethyl]-amino,N-[1-(acetylamino-phenyl)ethyl]-aminomethyl,N-[2-(acetylamino-phenyl)ethyl]-amino,N-(1-hydroxy-3-phenylprop-2-yl)-amino,N-(1-hydroxy-1-phenylprop-2-yl)-amino, N-(furylmethyl)-aminomethyl,N-(pyridylmethyl)-aminomethyl, N-benzyl-N-methylamino,N-benzyl-N-methyl-aminomethyl, N-fluorobenzyl-N-methyl-aminomethyl,N-(acetylamino-benzyl)-N-methyl-aminomethyl,N-methyl-N-(1-phenylethyl)-aminomethyl,N-(2-hydroxy-1-phenylethyl)-N-methylamino,N-[2-(acetylamino-phenyl)ethyl]-N-methylamino andN-methyl-N-(thienylmethyl)amino.

Suitable values of R^(a) include hydrogen, hydroxy and benzyl,especially hydrogen.

Suitably, R² and R³ independently represent hydrogen or methyl,especially hydrogen.

Suitably, R⁴ represents hydrogen or methyl.

Suitably, R⁵ and R⁶ are independently selected from hydrogen, methyl,ethyl, n-propyl, isopropyl, n-butyl, t-butyl, trifluoromethyl, phenyl,methylphenyl (especially 4-methylphenyl), benzyl and phenethyl.

Suitably, the substituent Z represents hydrogen, fluoro, cyano, hydroxy,methoxy, ethoxy, benzyloxy, methylamino-carbonyloxy, cyano-methoxy,aminocarbonyl-methoxy, methylsulphonyl, phenylsulphonyl, aminosulphonyl,N-methylamino-sulphonyl, N,N-dimethylamino-sulphonyl, amino,formylamino, acetylamino, trifluoromethyl-carbonylamino,benzyloxy-carbonylamino, methyl-sulphonylamino, ethyl-sulphonylamino,methylphenyl-sulphonylamino, N-methyl-(N-methylsulphonyl)-amino,N-methyl-(N-ethylsulphonyl)-amino,N-methyl-(N-trifluoromethylsulphonyl)-amino,N-ethyl-(N-methylsulphonyl)-amino, N-benzyl-(N-methylsulphonyl)-amino,N-benzyl-(N-ethylsulphonyl)-amino, acetyl, methoxycarbonyl,ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl,propylaminocarbonyl, butylaminocarbonyl, benzylaminocarbonyl orphenethyl-aminocarbonyl; or a group of formula (a), (b), (c) or (d) asdefined above.

In a particular embodiment, Z represents --SO₂ NR⁵ R⁶ in which R⁵ and R⁶are as defined above. In a subset of this embodiment, R⁵ and R⁶independently represent hydrogen or C₁₋₆ alkyl, especially hydrogen ormethyl. Particular values of Z in this context include aminosulphonyl,N-methylamino-sulphonyl and N,N-dimethylamino-sulphonyl, especiallyN-methylamino-sulphonyl.

In another embodiment, Z represents a group of formula (b) in which R⁴is hydrogen or methyl. In a subset of this embodiment, X and Y bothrepresent oxygen. In a particular aspect of this subset, the chiralcentre denoted by the asterisk * is in the (S) configuration.

A particular sub-class of compounds according to the invention isrepresented by the compounds of formula IIA, and salts and prodrugsthereof: ##STR7## wherein m is zero, 1, 2 or 3, preferably zero or 1;

n is 2, 3 or 4, preferably 2 or 3;

p is zero, 1 or 2;

R⁵ and R⁶ are as defined with reference to formula I above;

W¹ represents oxygen, sulphur or N--R¹² ; and

R¹¹ and R¹² independently represent hydrogen, C₁₋₆ alkyl, aryl,aryl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any of whichgroups may be optionally substituted.

Examples of suitable optional substituents on the groups R¹¹ and R¹²include halogen, cyano, trifluoromethyl, hydroxy, C₁₋₆ alkoxy, C₂₋₆alkylcarbonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₂₋₆alkylcarbonylamino, C₁₋₆ alkylsulphonylamino and C₁₋₆alkylaminosulphonylmethyl.

Particular values of R⁵ and R⁶ with reference to formula IIA aboveinclude hydrogen and C₁₋₆ alkyl, especially hydrogen or methyl.Suitably, one of R⁵ and R⁶ represents hydrogen and the other representshydrogen or methyl.

Particular values of R¹¹ and R¹² include hydrogen, methyl, benzyl,fluorobenzyl, methoxy-benzyl, acetylamino-benzyl, 1-phenylethyl,2-phenylethyl, 2-hydroxy-1-phenylethyl, 1-(acetylamino-phenyl)ethyl,2-(acetylamino-phenyl)ethyl, 1-hydroxy-3-phenylprop-2-yl,1-hydroxy-1-phenylprop-2-yl, furylmethyl, thienylmethyl andpyridylmethyl.

Typically, R¹¹ represents benzyl, fluorobenzyl, 1-phenylethyl or2-hydroxy-1-phenylethyl.

Typically, R¹² is hydrogen or methyl.

Another sub-class of compounds according to the invention is representedby the compounds of formula IIB, and salts and prodrugs thereof:##STR8## wherein the asterisk * denotes a chiral centre; R⁴ and Y are asdefined with reference to formula I above: and

m, n, p, W¹ and R¹¹ are as defined with reference to formula IIA above.

A further sub-class of compounds according to the invention isrepresented by the compounds of formula IIC, and salts and prodrugsthereof: ##STR9## wherein the asterisk * denotes a chiral centre; R⁴ andY are as defined with reference to formula I above; and

m, n, p, W¹ and R¹¹ are as defined with reference to formula IIA above.

In relation to formula IIB and IIC above, the chiral centre denoted bythe asterisk * is suitably in the (S) configuration.

Specific compounds within the scope of the present invention include:

(3S)-3-(N-benzyl)aminomethyl-1-[2-(5-(N-methyl)-aminosulphonylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

(3S)-3-(N-benzyl)aminomethyl-1-[2-(5-(aminosulphonylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

(3S)-3-(N-benzyl)aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

(3S)-3-[N-(R)-α-(hydroxymethyl)benzyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

(3S)-3-[N-(S)-α-methylbenzyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

4-[N-(R)-α-(hydroxymethyl)benzyl]amino-(S)-1-[3-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)propyl]piperidine;

(3S)-3-(N-benzyl-N-methyl)aminomethyl-(S)-1-[2-(5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

(3R)-3-[N-(S)-α-methylbenzyl-N-methyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

(3R)-3-[N-(S)-α-methylbenzyl-N-methyl]aminomethyl-(S)-1-[2-(5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

(3S)-3-[N-(4-fluorobenzyl)-N-methyl]aminomethyl-(S)-1-[2-(5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

and salts and prodrugs thereof.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the presentinvention. Typical unit dosage forms contain from 1 to 100 mg, forexample 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be , delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of migraine, a suitable dosage level is about 0.01 to250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, andespecially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

The compounds according to the invention wherein U represents C--R² andV represents N--R³, corresponding to the indole derivatives of formulaIE as defined above, may be prepared by a process which comprisesreacting a compound of formula III: ##STR10## wherein Z and E are asdefined above; with a compound of formula IV, or a carbonyl-protectedform thereof. ##STR11## wherein R², Q, M, R and R^(a) are as definedabove; followed, where required, by N-alkylation by standard methods tointroduce the moiety R³.

The reaction between compounds III and IV, which is an example of thewell-known Fischer indole synthesis, is suitably carried out by heatingthe reagents together under mildly acidic conditions, e.g. 4% sulphuricacid at reflux.

Suitable carbonyl-protected forms of the compounds of formula IV includethe dimethyl acetal or ketal derivatives.

The Fischer reaction between compounds III and IV may be carried out ina single step, or may proceed via an initial non-cyclising step at alower temperature to give an intermediate of formula V: ##STR12##wherein Z, E, Q, R², M, R and R^(a) are as defined above; followed bycyclisation using a suitable reagent, e.g. a polyphosphate ester.

The intermediates of formula IV, or carbonyl-protected forms thereof,may be prepared by reacting a compound of formula VI, or acarbonyl-protected form thereof, with a compound of formula VII:##STR13## wherein Q, R², M, R and R^(a) are as defined above, and L¹represents a suitable leaving group.

The leaving group L¹ is suitably a halogen atom, e.g. chlorine orbromine.

Where L¹ represents a halogen atom, the reaction between compounds VIand VII is conveniently effected by stirring the reactants under basicconditions in a suitable solvent, for example sodium carbonate orpotassium carbonate in 1,2-dimethoxyethane or N,N-dimethylformamide, ortriethylamine in tetrahydrofuran or acetonitrile, optionally in thepresence of catalytic sodium iodide.

In an alternative procedure, the compounds according to the inventionmay be prepared by a process which comprises reacting a compound offormula VII as defined above with a compound of formula VIII: ##STR14##wherein Z, E, Q, U and V are as defined above, and L² represents asuitable leaving group.

The leaving group L² is suitably an alkylsulphonyloxy orarylsulphonyloxy group, e.g. methanesulphonyloxy (mesyloxy) orp-toluenesulphonyloxy (tosyloxy).

Where L² represents an alkylsulphonyloxy or arylsulphonyloxy group, thereaction between compounds VII and VIII is conveniently carried out in asuitable solvent such as isopropanol/acetonitrile N,N-dimethylformamideor 1,2-dimethoxyethane, typically in the presence of a base such assodium carbonate or potassium carbonate, optionally in the presence ofcatalytic sodium iodide.

In one representative approach, the compounds of formula VIII wherein Urepresents CH, V represents NH and L² represents a mesyloxy or tosyloxygroup may be prepared by the sequence of steps illustrated in thefollowing reaction scheme (cf. Larock and Yum, J. Am. Chem. Soc., 1991,113, 6689): ##STR15## wherein Z, E and Q are as defined above, L³represents mesyloxy or tosyloxy, and TES is an abbreviation fortriethylsilyl.

In Step 1 of the reaction scheme, the aniline derivative IX is treatedwith iodine monochloride, typically in acetonitrile, in order tointroduce an iodine atom ortho to the amine moiety. Step 2 involves apalladium-mediated coupling reaction with the protected acetylenederivative TES--C.tbd.C--Q--OTES, typically using palladium acetate andtriphenylphosphine in the presence of lithium chloride and sodiumcarbonate, suitably in N,N-dimethylformamide at an elevated temperature.This is followed in Step 3 by removal of the TES moiety, ideally inrefluxing methanolic hydrochloric acid: followed in turn by mesylationor tosylation, suitably by using mesyl chloride or tosyl chloriderespectively in the presence of a base such as triethylamine orpyridine, typically in dichloromethane/acetonitrile.

In another representative approach, the compounds of formula VIIIwherein U represents CH, V represents NH, Q represents a propylene chainand L² represents a mesyloxy or tosyloxy group may be prepared byreacting 3,4-dihydro-2H-pyran with a compound of formula III as definedabove or a salt thereof, under a variant of the Fischer reactionconditions as described above for the reaction between compounds III andIV; followed by mesylation or tosylation of the 3-hydroxypropyl-indolederivative thereby obtained, typically by treatment with mesyl chlorideor tosyl chloride under standard conditions.

The Fischer reaction with 3,4-dihydro-2H-pyran is suitably brought aboutby heating an acid addition salt of the hydrazine derivative III,typically the hydrochloride salt, in an inert solvent such as dioxan, atthe reflux temperature of the solvent.

In a further procedure, the compounds according to the invention whereinU represents nitrogen and V represents N--R³, corresponding to theindazole derivatives of formula ID as defined above, may be prepared bya process which comprises cyclising a compound of formula X: ##STR16##wherein Z, E, Q, M, R and R^(a) are as defined above, and D¹ representsa readily displaceable group; followed, where required, by N-alkylationby standard methods to introduce the moiety R³.

The cyclisation of compound X is conveniently achieved in a suitableorganic solvent at an elevated temperature, for example in a mixture ofm-xylene and 2,6-lutidine at a temperature in the region of 140° C.

The readily displaceable group D¹ in the compounds of formula X suitablyrepresents a C₁₋₄ alkanoyloxy group, preferably acetoxy. Where D¹represents acetoxy, the desired compound of formula X may beconveniently prepared by treating a carbonyl compound of formula XI:##STR17## wherein Z, E, Q, M, R and R^(a) are as defined above; or aprotected derivative thereof, preferably the N-formyl protectedderivative; with hydroxylamine hydrochloride, advantageously in pyridineat the reflux temperature of the solvent; followed by acetylation withacetic anhydride, advantageously in the presence of a catalytic quantityof 4-dimethylaminopyridine, in dichloromethane at room temperature.

The N-formyl protected derivatives of the intermediates of formula XImay conveniently be prepared by ozonolysis of the corresponding indolederivative of formula XII: ##STR18## wherein Z, E, Q, M, R and R^(n) areas defined above; followed by a reductive work-up, advantageously usingdimethylsulphide.

The indole derivatives of formula XII may be prepared by methodsanalogous to those described in the accompanying Examples, or byprocedures well known from the art.

In a still further procedure, the compounds according to the inventionwherein U represents C--R² and V represents oxygen or sulphur,corresponding to the benzofuran or benzthiophene derivatives of formulaIC wherein V is oxygen or sulphur respectively, may be prepared by aprocess which comprises cyclising a compound of formula XIII: ##STR19##wherein Z, E, Q, R², M, R and R^(a) are as defined above, and V¹represents oxygen or sulphur.

The cyclisation of compound XIII is conveniently effected by usingpolyphosphoric acid or a polyphosphate ester, advantageously at anelevated temperature.

The compounds of formula XIII may be prepared by reacting a compound offormula XIV with a compound of formula XV: ##STR20## wherein Z, E, Q,R², V¹, M, R and R^(a) are as defined above, and Hal represents ahalogen atom.

The reaction is conveniently effected in the presence of a base such assodium hydroxide.

The hydroxy and mercapto derivatives of formula XIV may be prepared by avariety of methods which will be readily apparent to those skilled inthe art.

The hydrazine derivatives of formula III above may be prepared bymethods analogous to those described in EP-A-0548813 and WO-A-91/18897,as also may the aniline derivatives of formula IX.

Where they are not commercially available, the starting materials offormula VI, VII and XV may be prepared by the methods described in theaccompanying Examples, or by analogous procedures which will be apparentto those skilled in the art.

It will be understood that any compound of formula I initially obtainedfrom any of the above processes may, where appropriate, subsequently beelaborated into a further compound of formula I by techniques known fromthe art. For example, a compound of formula I wherein R^(x) is benzylinitially obtained may be converted into a compound of formula I whereinR^(x) is hydrogen typically by conventional catalytic hydrogenation, orby transfer hydrogenation using a hydrogenation catalyst such aspalladium on charcoal in the presence of a hydrogen donor such asammonium formate. Moreover, a compound of formula I wherein R¹ ishydroxy initially obtained may be converted into the correspondingcarbonyl compound (aldehyde or ketone) by treatment with a conventionaloxidising agent such as sulphur trioxide-pyridine complex; the resultingcarbonyl compound may then be converted in turn into a compound offormula I wherein R¹ represents --NHR^(y), suitably by a standardreductive amination procedure which comprises treating the carbonylcompound with the appropriate amine of formula R^(y) --NH₂ in thepresence of a suitable reducing agent, typically sodiumcyanoborohydride. Similarly, a compound of formula I wherein R¹represents --NHR^(y) initially obtained may be converted into a furthercompound of formula I wherein R¹ represents --NR^(x) R^(y), in whichR^(x) corresponds to the group --CH₂ R^(z), suitably by a reductiveamination procedure which comprises treating the compound of formula Iwherein R¹ represents --NHR^(y) with the appropriate aldehyde of formulaR^(z) --CHO in the presence of a reducing agent such as sodiumcyanoborohydride. In addition, a compound of formula I wherein R³ ishydrogen initially obtained may be converted into a compound of formulaI wherein R³ represents C₁₋₆ alkyl by standard alkylation techniques,for example by treatment with an alkyl iodide, e.g. methyl iodide,typically under basic conditions, e.g. sodium hydride indimethylformamide, or triethylamine in acetonitrile.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The novel compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The novel compounds may, for example, beresolved into their component enantiomers by standard techniques such aspreparative HPLC, or the formation of diastereomeric pairs by saltformation with an optically active acid, such as(-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organtic Synthesis. JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds in accordance with the present invention potently andselectively bind to the 5-HT_(1D)α receptor subtype, inhibitforskolin-stimulated adenylyl cyclase activity, and stimulate [³⁵S]-GTPγS binding to membranes from clonal cell lines expressing humancloned receptors.

5-HT_(1D)α /5-HT_(1D)β Radioligand Binding

Chinese hamster ovary (CHO) clonal cell lines expressing the human5-HT_(1D)α and 5-H_(1D)β receptors were harvested in PBS and homogenisedin ice cold 50 mM Tris-HCl (pH 7.7 at room temperature) with aKinematica polytron and centrifuged at 48,000 g at 4° C. for 11 min. Thepellet was then resuspended in 50 mM Tris-HCl followed by a 10 minincubation at 37° C. Finally the tissue was recentrifuged at 48,000 g,4° C. for 11 min and the pellet resuspended, in assay buffer(composition in mM: Tris-HCl 50, pargyline 0.01, CaCl₂ 4; ascorbate0.1%; pH 7.7 at room temperature) to give the required volumeimmediately prior to use (0.2 mg protein/ml). Incubations were carriedout for 30 min at 37° C. in the presence of 0.02-150 nM [3H]-5-HT forsaturation studies or 2-5 nM [3H]-5-HT for displacement studies. Thefinal assay volume was 1 ml. 5-HT (10 μM) was used to definenon-specific binding. The reaction was initiated by the addition ofmembrane and was terminated by rapid filtration through Whatman GF/Bfilters (presoaked in 0.3% PEI/0.5% Triton X) followed by 2×4 mlwashings with 50 mM Tris-HCl. The radioactive filters were then countedon a LKB beta or a Wallac beta plate counter. Binding parameters weredetermined by non-linear, least squares regression analysis using aniterative curve fitting routine, from which IC₅₀ (the molarconcentration of compound necessary to inhibit binding by 50%) valuescould be calculated for each test compound. The IC₅₀ values for bindingto the 5-HT_(1D)α receptor subtype obtained for the compounds of theaccompanying Examples were below 50 nM in each case. Furthermore, thecompounds of the accompanying Examples were all found to possess aselective affinity for the 5-HT_(1D)α receptor subtype of at least10-fold relative to the 5-HT_(1D)β subtype.

5-HT_(1D)α /5-HT_(1D)β Adenylyl Cyclase Assay

Studies were performed essentially as described in J. Pharmacol. Exp.Ther., 1986, 238, 248. CHO clonal cell lines expressing the human cloned5-HT_(1D)α and 5-HT_(1D)β receptors were harvested in PBS andhomogenised, using a motor driven teflon/glass homogeniser, in ice coldTris HCl-EGTA buffer (composition in mM: Tris HCl 10, EGTA 1, pH 8.0 atroom temperature) and incubated on ice for 30-60 min. The tissue wasthen centrifuged at 20,000 g for 20 min at 4° C., the supernatantdiscarded and the pellet resuspended in Tris HCl-EDTA buffer(composition in mM: Tris HCl 50, EDTA 5, pH 7.6 at room temperature)just prior to assay. The adenylyl cyclase activity was determined bymeasuring the conversion of α-[³³ P]-ATP to [³³ P]-cyclic AMP. A 10 μlaliquot of the membrane suspension was incubated, for 10-15 min, in afinal volume of 50 μl, at 30° C., with or without forskolin (10 μM), inthe presence or absence of test compound. The incubation bufferconsisted of 50 mM Tris HCl (pH 7.6 at room temperature), 100 mM NaCl,30 μM GTP, 50 μM cyclic AMP, 1 mM dithiothreitol, 1 mM ATP, 5 mM MgCl₂,1 mM EGTA, 1 mM 3-isobutyl-1-methylxanthine, 3.5 mM creatininephosphate, 0.2 mg/ml creatine phosphokinase, 0.5-1 μCi α-[³³ P]-ATP and1 nCi [³ H]-cyclic AMP. The incubation was initiated by the addition ofmembrane, following a 5 min preincubation at 30° C., and was terminatedby the addition of 100 μl SDS (composition in mM: sodium lauryl sulphate2%, ATP 45, cyclic AMP 1.3, pH 7.5 at room temperature). The ATP andcyclic AMP were separated on a double column chromatography system(Anal. Biochem., 1974, 58, 541) Functional parameters were determinedusing a least squares curve fitting programme ALLFIT (Am. J. Physiol.,1978, 235, E97) from which E_(max) (maximal effect) and EC₅₀ (the molarconcentration of compound necessary to inhibit the maximal effect by50%) values were obtained for each test compound. Of those compoundswhich were tested in this assay, the EC₅₀ values for the 5-HT_(1D)αreceptor obtained for the compounds of the accompanying Examples werebelow 500 nM in each case. Moreover, the compounds of the accompanyingExamples which were tested were all found to possess at least a 10-foldselectivity for the 5-HT_(1D)α receptor subtype relative to the5-HT_(1D)β subtype.

5-HT_(1D)α /5-HT_(1D)β GTPγS Binding

Studies were performed essentially as described in Br. J. Pharmacol.,1993, 109, 1120. CHO clonal cell lines expressing the human cloned5-HT_(1D)α and 5-HT_(1D)β receptors were harvested in PBS andhomogenised using a Kinematica polytron in ice cold 20 mM HEPEScontaining 10 mM EDTA, pH 7.4 at room temperature. The membranes werethen centrifuged at 40,000 g, 4° C. for 15 min. The pellet was thenresuspended in ice cold 20 mM HEPES containing 0.1 mM EDTA, pH 7.4 atroom temperature and recentrifuged at 40,000 g, 4° C. for 15-25 minutes.The membranes were then resuspended in assay buffer (composition in mM:HEPES 20, NaCl 100, MgCl₂ 10, pargyline 0.01; ascorbate 0.1%; pH 7.4 atroom temperature) at a concentration of 40 μg protein/ml for the5-HT_(1D)α receptor transfected cells and 40-50 μg protein/ml for the5-HT_(1D)β receptor transfected cells. The membrane suspension was thenincubated. in a volume of 1 ml, with GDP (100 μM for 5-HT_(1D)α receptortransfected cells, 30 μM for the 5-HT_(1D)β receptor transfected cells)and test compound at 30° C. for 20 min and then transferred to ice for afurther 15 min. [³⁵ S]-GTPγS was then added at a final concentration of100 pM and the samples incubated for 30 min at 30° C. The reaction wasinitiated by the addition of membrane and was terminated by rapidfiltration through Whatman GF/B filters and washed with 5 ml water. Theradioactive filters were then counted on a LKB beta counter. Functionalparameters were determined by a non-linear, least squares regressionanalysis using an iterative curve fitting routine, from which E_(max)(maximal effect) and EC₅₀ (the molar concentration of compound necessaryto inhibit the maximal effect by 50%) values were obtained for each testcompound. Of those compounds which were tested in this assay, the EC₅₀values for the 5-HT_(1D)α receptor obtained for the compounds of theaccompanying Examples were below 500 nM in each case. Moreover, thecompounds of the accompanying Examples which were tested were all foundto possess at least a 10-fold selectivity for the 5-HT_(1D)α receptorsubtype relative to the 5-HT_(1D)β subtype.

EXAMPLE 1(3S)-3-(N-Benzyl)aminomethyl-1-[2-(5-(N-(methyl)amino-sulphonylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine2.1 Hydrogen Oxalate 0.7 Diethyl Etherate

1. Intermediate 1: (3S)-N(H)-3-(N-Benzyl)aminomethylpyrrolidine

a) (3R)-N-tert-Butyloxycarbonyl-3-hydroxymethylpyrrolidine

A mixture of (3R)-N-[(R)-1-phenylethyl]-3-(hydroxymethyl)pyrrolidine (J.Med. Chem., 1990, 33(1), 71; 17.0 g, 82.8 mmol),di-tert-butyldicarbonate (21.7 g, 99.4 mmol), Pearlman's catalyst (4.28g, 25% w/w), methanol (300 ml) and water (40 ml) was hydrogenated on aParr shake apparatus, at 40 psi, for 2.25 h. The mixture was filteredthrough a pad of celite and the pad washed with ethanol. The combinedfiltrate and washings were evaporated and the residue chromatographed onsilica gel eluting with CH₂ Cl₂ /MeOH (95:5) to give thetitle-pyrrolidine (16.73 g, 100%), δ (250 MHz, D₆ -DMSO) 1.39 (9H, s,OC(Me)₃), 1.31-1.64 (2H, m, CH₂), 1.79-1.88 (1H, m, CH), 2.19-2.31 (1H,m, CH of CH₂), 2.95 (1H, dd, J=10.7 and 7.0Hz, CH of CH₂), 3.11-3.35(4H, m, 2 of CH₂), 4.67 (1H, t, J=5.3Hz, OH).

b) (3R)-N-tert-Butyloxycarbonyl-3-methylsulphonyloxymethylpyrrolidine

A solution of methane sulphonyl chloride (3.37 g, 29.39 mmol) in CH₂ Cl₂(30 ml) was added dropwise to a solution of(3R)-N-tert-butyloxycarbonyl-3-hydroxymethylpyrrolidine (5.4 g, 26.7mmol) and anhydrous triethylamine (2.97 g, 29.39 mmol), in CH₂ Cl₂ (100ml), at -15° C. The mixture was warmed to room temperature and stirredfor 16 h before adding saturated K₂ CO₃ solution (50 ml) and dilutingwith CH₂ Cl₂ (100 ml). The aqueous was separated and extracted furtherwith CH₂ Cl₂ (2×100 ml). The combined extracts were dried (Na₂ SO₄) andevaporated to give the title-mesylate (7.5 g, 100%), δ (250 MHz, CDCl₃)1.46 (9H, s, OC(Me)₃), 1.62-1.84 (1H, m, CH of CH₂), 2.00-2.14 (1H, m,CH of CH₂), 2.58-2.72 (1H, m, CH), 3.04 (3H, s, Me), 3.08-3.62 (4H, m, 2of CH₂), 4.11-4.33 (2H, m, CH₂ OMs).

c) (3S)-N-tert-Butyloxycarbonyl-3-N-(benzyl)aminomethylpyrrolidine

A solution of the preceding mesylate (5.0 g, 17.90 mmol) and benzylamine(9.8 ml, 89.7 mmol) in toluene (25 ml) was heated at reflux for 18 h.The mixture was evaporated under high vacuum and the residue taken up inethyl acetate (200 ml) and washed with water (×3). The organic layer wasdried (MgSO₄) and evaporated and the crude product chromatographed onsilica gel eluting with CH₂ Cl₂ /MeOH (98:2) to give the desired product(4.9 g, 94%), δ (250 MHz, CDCl₃) 1.45 (9H, s, OC(Me)₃), 1.52-1.64 (1H,m, CH), 1.92-2.08 (1H, m, CH of CH₂), 2.27-2.40 (1H, m, CH of CH₂),2.60-2.68 (2H, m, CH₂), 2.93-3.08 (1H, m, CH of CH₂), 3.18-3.60 (3H, m,CH₂ and CH of CH₂), 3.80 (2H, s, NHCH₂ Bn), 7.26-7.36 (5H, m, Ar--H).

d) (3S)-N(H)-3-(N-Benzyl)aminomethyl Pyrrolidine

A solution of the preceding benzylamine (4.9 g, 16.8 mmol) in 90% formicacid (90 ml) was stirred at room temperature for 18.5 h. The reactionwas quenched by addition of MeOH and the solvents were removed undervacuum. The residue was dissolved in a minimum volume of H₂ O, basifiedwith saturated K₂ CO₃ solution and extracted with n-butanol (3×100 ml).The combined extracts were evaporated in vacuo and the inorganicsremoved by trituration with CH₂ Cl₂ and filtration. The filtrate wasdried MgSO₄) and evaporated to give the title-pyrrolidine (3.24 g,100%), δ (360 MHz, CDCl₃) 1.42-1.60 (1H, m, CH), 1.94-2.03 (1H, m, CH ofCH₂), 2.24-2.36 (1H, m, CH of CH₂), 2.58-2.73 (3H, m, CH₂ and CH ofCH₂), 2.94-3.19 (3H, m, CH₂ and CH of CH₂), 3.79 (2H, m, NHCH₂ Bn),7.23-7.35 (5H, m, Ar--H).

2. Intermediate 2:2-[5-(N-(Methyl)aminosulphonyl-methyl)-1H-indol-3-yl]ethyl Alcohol

A. 2-Iodo-4-(N-(methyl)aminosulphonylmethyl)phenyl Aniline

a) 1-(N-(Methyl)aminosulphonylmethyl)-4-nitrobenzene

A mixture of 4-nitrobenzyl bromide (100.0 g, 0.46 mol), sodium sulphite(84.8 g, 0.67 mol) and water (316 ml) was heated at 90° C. for 5 h. Thesolution was cooled and the resultant solid filtered and washed withdiethyl ether. The product was dried under vacuum at 60° C. (95 g, 86%).Phosphorus pentachloride (78 g, 0.375 mol) was added to sodium4-nitrobenzylsulphonate (60 g, 0.25 mol) and the mixture heated at 90°C. for 2 h. The mixture was cooled and volatile material removed undervacuum. The residue was dissolved in dichloromethane (500 ml) and water(150 ml). The organic layer was separated, dried over anhydrous sodiumsulphate, filtered and evaporated to give 4-nitrobenzyl sulphonylchloride (48.9 g, 83%) which was pure by ¹ H NMR. Methylamine gas wasbubbled through a solution of 4-nitrobenzyl sulphonyl chloride (37.9 g,0.16 mol), in dichloromethane (325 ml), until uptake had ceased (0.5 h).The resulting solid was filtered, washed with H₂ O and dried undervacuum to give the title-sulphonamide (32.5 g, 88%), δ (250 MHz, D₆-DMSO) 2.61 (3H, s, Me), 4.55 (2H, s, CH₂), 7.06 (1H, s, NH), 7.66 (2H,d, J=8.7Hz, Ar--H), 8.25 (2H, d, J=8.7Hz, Ar--H).

b) 2-Iodo-4-(N-(methyl)aminosulphonylmethyl)phenylaniline

A mixture of the preceding 4-nitro-N-methylbenzenemethane sulphonamide(28.86 g, 0.126 mol), H₂ O (100 ml), ethanol (250 ml), 5N HCl (25 ml)and 10% Pd-C (3.0 g) was hydrogenated on a Parr shake apparatus at 50psi for 4 h. The catalyst was removed by filtration through celite andthe solvents removed under vacuum. The residue was dissolved in water(200 ml) and basified with K₂ CO₃. The precipitated product was filteredoff, washed with water and hexane and dried under vacuum at 45° C. togive the desired aniline (21.45 g, 85%) which was pure by ¹ H NMR. To astirred suspension of the preceding aniline (21.45 g, 0.107 mol) inacetonitrile (250 ml) was added a solution of iodine monochloride (17.41g, 0.107 mol), in acetonitrile (50 ml), dropwise over 1 h. The mixturewas stirred at room temperature for 16 h and then partitioned betweenethyl acetate (500 ml) and 20% aqueous sodium thiosulphate (300 ml). Theorganic layer was separated, washed with H₂ O (500 ml) and brine (100ml) and dried (Na₂ SO₄). The solvent was removed under vacuum and thecrude product chromatographed on silica gel eluting with ethylacetate/hexane (1:1) to give the title-iodoaniline (9.0 g, 26%), δ (250MHz, D₆ -DMSO) 2.51 (3H, d, J=7.4Hz, Me), 4.11 (2H, s, CH₂), 5.29 (2H,s, NH₂), 6.72 (1H, d, J=8.3Hz, Ar--H), 6.81 (1H, q, J=7.4Hz, NH), 7.06(1H, dd, J=2.0 and 8.3Hz, Ar--H), 7.53 (1H, d, J=2.0 Hz, Ar--H).

B. 1,4-bis-Triethylsilyl-3-butyn-1-ol

n-Butyl lithium (776 ml of a 2.5M solution in hexane, 1.94 mol) wasadded over a 2 h period to a stirred solution of 3-butyn-1-ol (68 g,0.97 mol), in anhydrous THF (1.16 l), at -30° C. The mixture was stirredat -30° C. for 1 h (dianion precipitates out) and triethylsilyl chloride(300 g, 1.99 mol) was then added dropwise, ensuring that the temperatureremained below -20° C. The solution was stirred at -10° C. for 1 h andthen at room temperature for 1 h. Hexane (1.36 l) and Na₂ CO₃ solution(7.0 g in 700 ml of H₂ O) were added to the reaction mixture, at -10°C., and the layers separated. The aqueous layer was extracted withhexane and the combined extracts were washed with water, dried (Na₂ SO₄)and evaporated to give the title-bis triethylsilyl butynol (289 g,100%), δ (250 MHz, CDCl₃) 0.80-0.94 (12H, m, 6 of SiCH₂ CH₃), 1.22-1.32(18H, m, 6 of SiCH₂ CH₃), 2.76 (2H, t, J=7.3Hz, CH₂), 4.00 (2H, t,J=7.3Hz, CH₂).

C. 2-[5-(N-(Methyl)aminosulphonylmethyl)-1H-indol-3-yl]ethyl Alcohol

A mixture of 2-iodo-4-(N-(methyl)aminosulphonylmethyl)phenyl aniline (10g, 30.7 mmol), 1,4-bis-triethylsilyl-3-butyn-1-ol (10.97 g, 36.8 mmol)sodium carbonate (16.26 g, 153.4 mmol) and anhydrous DMF (500 ml) wasdegassed with N₂ for 0.5 h. Pd(OAc)₂ (0.7 g, 3.1 mmol) was added and themixture heated at 100° C. for 6 h. The DMF was removed under vacuum andthe residue partitioned between EtOAc (250 ml) and water (250 ml). Thesolutions were passed through celite to remove insolubles and theaqueous layer separated and extracted further with ethyl acetate (4×200ml). The combined organics were dried (Na₂ SO₄) and evaporated. Theresidue was dissolved in methanol (100 ml) and 5N hydrochloric acid (30ml) was added. The mixture was stirred at room temperature for 2 h andthe solvent then removed under vacuum and the residue neutralised withsaturated K₂ CO₃ solution. The aqueous was extracted with EtOAc (200 ml)and n-butanol (2×200 ml) and the combined extracts evaporated undervacuum The residue was chromatographed on silica gel eluting with CH₂Cl₂ /MeOH/NH₃ (60:8:1) to give the title-indole (5.39 g, 66%), mp114-116° C., δ (250 MHz, D₆ -DMSO) 2.54 (3H, d, J=4.8Hz, MeNH), 2.83(2H, t, J=7.5Hz, CH₂), 3.60-3.69 (2H, m, CH₂ --OH), 4.34 (2H, s, CH₂),4.65 (1H, t, J=5.4Hz, OH), 6.78 (1H, q, J=4.8Hz, MeNH), 7.06 (1H, dd,J=2.2 and 8.3Hz, Ar--H), 7.16 (1H, d, J=2.2Hz, Ar--H), 7.31 (1H, d,J=8.3Hz, Ar--H), 7.51 (1H, s, Ar--H), 10.86 (1H, s, NH).

3.(3S)-3-(N-Benzyl)aminomethyl-1-[2-(5-(N-(methyl)aminosulphonylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine2.1 Hydrogen Oxalate 0.7 Diethyl Etherate

Methane sulphonyl chloride (0.32 g, 2.80 mmol) was added to a stirredsolution of 2-[5-(N-(methyl)aminosulphonylmethyl)-1H-indol-3-yl]ethylalcohol (0.50 g, 1.87 mmol) and triethylamine (0.38 g, 3.73 mmol), indichloromethane (15 ml) and acetonitrile (15 ml), at 0° C. The mixturewas warmed to room temperature and stirred for 3 h. Ethyl acetate (70ml) was added to the mixture and the solution washed with water (40 ml)and brine (40 ml). The organic was dried (MgSO₄) and evaporated. Theresidue was dissolved in anhydrous acetonitrile (7 ml) and IPA (55 ml)and Na₂ CO₃ (0.26 g, 2.5 mmol) and Intermediate 1 (0.47 g, 2.5 mmol)were added. The mixture was heated at reflux for 16 h and then cooled toroom temperature and the insolubles filtered off. The solvent wasremoved under vacuum and the residue chromatographed on silica geleluting with CH₂ Cl₂ /MeOH/NH₃ (60:8:1) and then again on alumina(Activity III) eluting with CH₂ Cl₂ /MeOH (98:2) to give thetitle-ethylpyrrolidine (58 mg, 8%). The 2.1 hydrogen oxalate 0.7 diethyletherate salt was prepared, mp 224-226° C., (Found: C, 54.74, H, 5.99,N, 7.95. C₂₄ H₃₂ N₄ SO₂.2.1(C₂ H₂ O₄).0.7(Et₂ O) requires C, 54.63, H.6.39, N, 8.22%), m/e 441 (M+1)⁺, δ (360 MHz, D₆ -DMSO) 1.70-1.84 (1H, m,CH), 2.12-2.26 (1H, m, CH), 2.50 (3H, s, MeNH), 2.66-2.80 (1H, m, CH),2.94-3.56 (10H, m, 5 of CH₂), 4.13 (2H, s, CH₂), 4.34 (2H, s, CH₂), 6.81(1H, br s, NH), 7.12 (1H, d, J=8.4Hz, Ar--H), 7.26 (1H, s, Ar--H), 7.36(1H, d J=8.4Hz, Ar--H), 7.40-7.52 (5H, m, Ar--H), 7.56 (1H, s, Ar--H),11.04 (1H, s, NH).

EXAMPLE 2(3S)-3-(N-Benzyl)aminomethyl-1-[2-(5-(aminosulphonylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine2.0 Hydrogen Oxalate 0.75 Hydrate

1. Intermediate 3: 2-[5-(Aminosulphonylmethyl)-1H-indol-3-yl]ethylAlcohol

Prepared from 4-nitrobenzene methane sulphonamide using the proceduresdescribed for Intermediate 2, mp 173-175° C., δ, (D₆ -DMSO) 2.83 (2H, t,J=7.4Hz, CH₂), 3.61-3.69 (2H, m, CH₂), 4.29 (2H, s, CH₂ SO₂), 4.64 (1H,t, J=5.3Hz, OH), 6.70 (2H, s, NH2), 7.06 (1H, dd, J=1.6 and 8.4Hz,Ar--H), 7.16 (1H, d, J=1.6Hz, Ar--H), 7.31 (1H, d, J=8.4Hz, Ar--H), 7.50(1H, s, Ar--H), 10.84 (1H, s, NH).

2.(3S)-3-(N-Benzyl)aminomethyl-1-[2-(5-(aminosulphonylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine2.0 Hydrogen Oxalate 0.75 Hydrate

Prepared from Intermediates 1 and 3 using the procedure described forExample 1. The 2.0 hydrogen oxalate 0.75 hydrate salt was prepared, mp203-205° C., (Found: C, 52.52, H, 5.90, N, 8.72; C₂₃ H₃₀ N₄ SO₂.2(C₂ H₂O₄).0.75H₂ O requires C, 52.29, H. 5.77, N, 9.03%) m/e 426 (M+1)⁺, δ(360 MHz, D₆ -DMSO) 1.68-1.82 (1H, m, CH), 2.12-2.24 (1H, m, CH),2.68-2.78 (1H, m, CH), 2.98-3.54 (1OH, m, 5 of CH₂), 4.11 (2H, s, CH₂),4.31 (2H, s, CH₂), 6.72 (2H, s, NH₂), 7.11 (1H, d, J=1.5 and 8.4Hz,Ar--H), 7.25 (1H, d, J=1.5Hz, Ar--H), 7.35 (1H, d, J=8.4Hz, Ar--H),7.40-7.52 (5H, m, Ar--H), 7.55 (1H, s, Ar--H), 11.02 (1H, s, NH).

EXAMPLE 3 (3S)-3-(N-Benzyl)aminomethyl-(S)-1-[2-(5-(2-oxo-13-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine. 3.0 HydrogenOxalate

1. Intermediate 4:(S)-2-[5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl]ethyl Alcohol

a) (S)-4-(4-Aminobenzyl)-1,3-oxazolidin-2-one

Prepared as described in WO 91/18897.

(b) (S)-4-(3-Iodo-4-aminobenzyl)-1,3-oxazolidin-2-one

A solution of iodine monochloride (4.84 g, 29.8 mmol) in methanol (35ml) was added dropwise to a stirred mixture of(S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one (5.2 g, 27.0 mmol) andcalcium carbonate (5.42 g, 54.2 mmol) in methanol (115 ml), at -40° C.The reaction was allowed to warm to room temperature and stir for 16 h.The solvent was removed under reduced pressure, the residue taken upinto ethyl acetate (300 ml) and washed with 20% aqueous sodiumthiosulphate (100 ml). The organic layer was separated, washed withwater (50 ml) and brine (50 ml), dried (Na₂ SO₄) and evaporated. Thecrude product was chromatographed on silica gel eluting with CH₂ Cl₂/MeOH/98:2 to give the title-iodoaniline (3.88, 45%), δ (250 MHz, D₆-DMSO) 2.55-2.60 (2H, m, CH₂), 3.90-3.99 (2H, m, CH₂ O), 4.19-4.28 (1H,m, CHNH), 5.09 (2H, s, NH₂), 6.69 (1H, d, J=8.2Hz, Ar--H), 6.95 (1H, dd,J=1.9 and 8.2Hz, Ar--H), 7.44 (1H, d, J=1.9Hz, Ar--H). 7.74 (1H, s, NH).

c) (S)-2-[5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1 H-indol-3-yl]ethylAlcohol

Prepared from (S)-4-(3-iodo-4-aminobenzyl)-1,3-oxazolidin-2-one and1,4-bis-triethylsilyl-3-butyn-1-ol as described for Intermediate 2, δ(360 MHz, D₆ -DMSO) 2.74-2.91 (4H, m, 2 of CH₂), 3.64 (2H, t, J=7.3Hz,CH₂), 4.00-4.08 (2H, m, CH₂), 4.20-4.26 (1H, m, CH), 6.92 (1H, dd, J=1.4and 8.2Hz. Ar--H), 7.10 (1H, s, Ar--H), 7.25 (1H, d, J=8.2Hz, Ar--H),7.36(1H, s, Ar--H), 7.75 (1H, s, NH), 10.69 (1H, s. NH).

2.(3S)-3-(N-Benzyl)aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine.3.0 Hydrogen Oxalate

Prepared from Intermediates 1 and 4 using the procedure described forExample 1. The 3.0 hydrogen oxalate salt was prepared, mp 196-197° C.,(Found: C, 54.46, H, 5.12, N, 7.63. C₂₆ H₃₂ N₄ O₂. 3.0 (C₂ H₂ O₄)requires C, 54.70, H, 5.45, N, 7.97%), m/e 433 (M+1)⁺, δ (360 MHz, D₆-DMSO) 1.72-1.86 (1H, m, CH), 2.14-2.27 (1H, m, CH), 2.68-3.64 (13H, m,6 of CH₂ and CH), 3.99-4.24 (2H, m, CH₂), 4.16 (2H, s, CH₂), 4.20-4.26(1H, m, CH), 6.98 (1H, d, J=8.6Hz, Ar--H), 7.20 (1H, s, Ar--H), 7.29(1H, d, J=8.6Hz, Ar--H), 7.38-7.54 (6H, m, Ar--H), 7.80 (1H, s, NH),10.91 (1H, s, NH).

EXAMPLE 4(3S)-3-[N-(R)-α-(Hydroxymethyl)benzyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine.2.2 Hydrogen Oxalate 0.5 Hemihydrate

1. Intermediate 5:(3S)-N(H)-3-[(R)-α-(Hydroxymethyl)benzyl]aminomethylpyrrolidine

a)(3S)-N-tert-Butyloxycarbonyl-3-[(R)-α(hydroxymethyl)benzyl]aminomethylpyrrolidine

A solution of (R)-(-)-phenylglycinol (2.20 g, 16.1 mmol) and(3R)-N-tert-butyloxycarbonyl-3-methylsulphonyloxymethylpyrrolidine(Intermediate 1 part b; 1.0 g, 3.58 mmol), in toluene (20 ml), washeated at 150° C. for 6 h in a sealed pressure tube (Aldrich). Thesolvent was then removed under vacuum and the residue taken up intoethyl acetate (200 ml) and washed with water (×4). The organic was dried(MgSO₄) and evaporated and the crude product chromatographed on silicagel eluting with CH₂ Cl₂ /MeOH (97:3) to give thetitle-α-(hydroxymethyl) benzylaminomethylpyrrolidine (1.0 g, 87%), δ(360 MHz,CDCl₃) 1.45 (9H, s, OC(Me)₃), 1.52-2.60 (5H, m, CH₂ and CH),2.90-3.76 (7H, m, 3 of CH₂ and CH), 7.25-7.39 (5H, m, Ar--H).

b) (3S)-N(H)-3-[(R)-α-(Hydroxymethyl)benzyl]aminomethylpyrrolidine

Prepared from the preceding N-Boc pyrrolidine using the proceduredescribed for Intermediate 1 part d, δ (250 MHz,CDCl₃) 1.25-1.45 (1H, m,CH of CH₂), 1.83-1.97 (1H, m, CH of CH₂), 2.14-2.61 (4H, m, 2 of CH₂),2.80-3.09 (3H, m, CH₂ and CH), 3.46-3.76 (3H, m, CH₂ and CH), 7.25-7.38(5H, m, Ar--H).

2.(3S)-3-[N-(R)-α-(Hydroxymethyl)benzyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine2.2 Hydrogen Oxalate 0.5 Hemihydrate

Prepared from Intermediates 4 and 5 using the procedure described forExample 1. The 2.2 hydrogen oxalate 0.5 hemihydrate salt was prepared,mp 115-117° C., (Found: C, 56.37, H, 6.19, N, 8.67. C₂₇ H₃₄ N₄ O₃. 2.2(C₂ H₂ O₄). 0.5H₂ O requires C, 56.32, H, 5.93, N, 8.37%), m/e 463(M+1)⁺, δ (360 MHz, D₆ -DMSO) 1.60-1.76 (1H, m, CH of CH₂), 2.08-2.22(1H, m, CH of CH₂), 2.46-4.68 (19H, m, 8 of CH₂ and 3 of CH), 6.98 (1H,d, J=8.4Hz, Ar--H), 7.20 (1H, s, Ar--H), 7.29 (1H, d, J=8.4Hz, Ar--H),7.32-7.46 (6H, m, Ar--H), 7.80 (1H, s, NH), 10.90 (1H, s, NH).

EXAMPLE 5(3S)-3-[N-(S)-α-Methylbenzyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine.2.4 Hydrogen Oxalate

Prepared from(S)-2-[5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl]ethyl alcoholand (3S)-N(H)-3-(N-(S)-α-methylbenzyl)aminomethyl pyrrolidine using theprocedures described for Example 4. The 2.4 hydrogen oxalate salt wasprepared, mp 115-117° C., (Found: C, 57.77, H, 5.93, N, 8.77. C₂₇ H₃₄ N₄O₂ requires C, 57.64, H, 5.90, N, 8.45%), m/e 447 (M+1)⁺. δ (360 MHz, D₆-DMSO) 1.51 (2H, d, J=6.7Hz, Me), 1.60-1.72 (1H, m, CH of CH₂),2.10-2.20 (1H, m, CH of CH₂), 2.48-4.60 (17H, m, 7-CH₂ and 3 of CH),6.97 (1H, d, J=8.3Hz, Ar--H), 7.19 (1H, s, Ar--H), 7.28 (1H, d, J=8.3Hz,Ar--H), 7.34-7.52 (6H, Ar--H and NH), 7.80 (1H, s, Ar--H), 10.89 (1H, s,NH).

EXAMPLE 64-[N-(R)-α-(Hydroxymethyl)benzyl]amino-(S)-1-[3-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)propyl]piperidine.2.15 Hydrogen Oxalate

1. (S)-3-[5-(2-oxo-1,3-oxazolidin-4-yl)methyl)-1H-indol-3-yl]propan-1-ol

The title compound was prepared in 61% yield from(S)-4-(3-iodo-4-aminobenzyl)-1,3-oxazolidin-2-one and1,5-bis-triethylsilyl-4-pentyn-1-ol as described for Intermediate 2. δ(360 MHz, DMSO-d₆) 1.78 (2H, qn, J=7.9Hz), 2.69 (2H, t, J=7.4Hz), 2.77(1H, dd, J=13.5 and 7.1 Hz), 2.89 (1H, dd, J=13.5 and 4.6Hz), 3.46 (2H,q, J=5.3Hz), 3.98-4.08 (2H, m), 4.18-4.28 (1H,m), 4.42 (1H, t, J=5.1Hz), 6.92 (1H, dd, J=8.3 and 1.5Hz), 7.06 (1H, d, J=2.1 Hz), 7.24 (1H,d, J=8.3Hz), 7.35 (1H, s). 10.66 (1H, s); m/z (ES) 275 (M⁺ +1).

2. 4-[N-(R)-α-(Hydroxymethyl)benzyl]aminopiperidine

To a stirred solution of N-tert-butyloxycarbonyl-4-piperidinone (2 g, 10mmol), (R)-(-)-phenylglycinol (1.65 g, 12 mmol), and glacial acetic acid(2.29 ml, 40 mmol) in methanol (200 ml) was added sodiumcyanoborohydride (754 mg, 12 mmol). After being stirred at roomtemperature, under nitrogen, for 16 hours, the mixture was basified with4N sodium hydroxide and the methanol was removed under vacuum. Theresidue was diluted with water (35 ml) and the product extracted withdiethyl ether (2×200 ml), washed with brine (1×40 ml), dried (Na₂ SO₄)and concentrated. Flash chromatography (silica gel,dichloromethane-methanol-ammonia, 95:5:0.5) of the residue gave 2.91 g(90.9%) ofN-tert-butyloxycarbonyl-4-[N-(R)-α-(hydroxymethyl)benzyl]aminopiperidine.

A solution of the above BOC-protected piperidine (2.9 g) intrifluoroacetic acid (40 ml) and dichloromethane (50 ml) was allowed tostand at room temperature for 16 hours. Solvents were removed undervacuum and the residue was azeotroped with toluene-ethanol (5:1, 150ml). The residue was dissolved in 4N sodium hydroxide, extracted withdichloromethane (3×150 ml) and the combined organic solutions werewashed with brine (1×50 ml), then dried (Na₂ SO₄) and concentrated.Crystallisation from ethyl acetate-hexane (1:10, 200 ml) afforded thetitle compound as white crystals (1.4 g, 70.4%): δ (360 MHz, DMSO-d₆)0.96-1.12 (2H, m), 1.52 (1H, d, J=12.0 Hz), 1.78-2.06 (2H, br s and d,J=12.6Hz) 2.17-2.32 (3H, m), 2.76-2.90 (2H, m), 3.26 (1H, t, J=8.5Hz),3.40 (1H, dd, J=10.5 and 4.5Hz), 3.83 (1H, dd, J=8.5 and 4.5Hz), 4.82(1H, br s), 7.27-7.37 (5H, m); m/z (ES) 221 (M⁺ +1).

3.4-[N-(R)-α-(Hydroxymethyl)benzyl]amino-(S)-1-[3-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)propyl]piperidine.2.15 Hydrogen Oxalate

The title compound free base was prepared from the products of steps 1and 2 using a similar method to that described for Example 1. Theoxalate salt was prepared from ethanol: mp 156-163° C.; (Found: C.57.85; H, 5.97; N, 8.63. C₂₈ H₃₆ N₄ O₃ ×2.15 C₂ H₂ O₄ requires: C,57.89. H, 6.06: N, 8.36%); m/z (ES) 477 (M⁺ +1); δ (360 MHz, DMSO-d₆)1.66-1.85 (2H, m), 1.92-2.18 (4H, m), 2.62-3.00 (9H, m), 3.30-3.42 (2H,m), 3.58-3.70 (2H, m), 3.98-4.10 (2H, m), 4.14-4.28 (2H, m), 6.95 (1H,d, J=8.3Hz), 7.11 (1H, s), 7.26 (1H, d, J=8.3Hz), 7.30-7.52 (4H, m),7.79 (1H, s), 10.77 (1H, s).

EXAMPLE 7(3S)-3-(N-Benzyl-N-methyl)aminomethyl-(S)-1-[2-(5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine.Sesquioxalate. Hemihydrate

1. Intermediate 6:(S)-2-[5-(3-Methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl]ethylAlcohol

a) (S)-3-Methyl-4-(4-aminobenzyl)-1,3-oxazolidin-2-one

Prepared as described in WO 91/18897.

b)(S)-2-[5-(3-Methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl]ethylAlcohol

Prepared from (S)-3-methyl-4-(3-iodo-4-aminobenzyl)-1,3-oxazolidin-2-oneand 1,4-bis-triethylsilyl-3-butyn-1-ol as described for Intermediate 2,δ (360 MHz, D₆ -DMSO) 2.72-2.84 (6H, m, CH of CH₂, CH₂ and N--Me), 3.13(1H, dd, J=3.8 and 13.5Hz, CH of CH₂), 3.61-3.67 (2H, m, CH₂), 3.94-4.02(2H, m, CH₂), 4.11-4.17 (1H, m, CH), 4.58 (1H, t, J=5.3Hz, OH), 6.93(1H, dd, J=1.5 and 8.3Hz, Ar--H), 7.10 (1H, d. J=1.5Hz, Ar--H), 7.26(1H, d, J=8.3Hz, Ar--H), 7.38 (1H, s, Ar--H), 10.72 (1H, s, NH).

2. Intermediate 7:(3S)-N(H)-3-(N-Benzyl-N-methyl)-aminomethylpyrrolidine

Prepared from (3R)-N-tert-butyloxycarbonyl-3-hydroxymethylpyrrolidineand N-methylbenzylamine using the procedures described for Intermediate1, 6 (250 MHz, D₆ -DMSO) 1.41-1.55 (1H, m, CH of CH₂), 1.89-2.02 (1H, m,CH of CH₂), 2.11 (3H, s, Me), 2.31 (2H, d, J=7.5Hz, CH₂ NMe), 2.38-2.52(1H, m, CH), 2.73 (1H, dd, J=6.9 and 11.3Hz, CH of CH₂), 2.95-3.23 (5H,m, 2 of CH₂ and CH of CH₂), 3.46 (2H, ABq, J=13.4Hz, NCH₂ --Ar),7.19-7.36 (5H, m, Ar--H).

3.(3S)-3-(N-Benzyl-N-methyl)aminomethyl-(S)-1-[2-(5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine.Sesquioxalate. Hemihydrate

Prepared from Intermediates 6 and 7 using the procedure described forExample 1. The sesquioxalate hemihydrate salt was prepared, mp 102-104°C., (Found: C, 61.73; H, 7.02; N, 9.02. C₂₈ H₃₆ N₄ O₂. 1.5(C₂ H₂ O₄)0.5H₂ O) requires C, 61.58; H, 6.67; N, 9.26%), m/e 461 (M+1)⁺, δ (360MHz, D₆ -DMSO) 1.60-1.72 (1H, m, CH of CH₂), 2.08-2.20 (1H, m, CH ofCH₂), 2.17 (3H, s, N--Me), 2.44-4.16 (18H, m, 2 of CH and 8 of CH₂),2.83 (3H, s, N--Me), 7.00 (1H, d, J=8.5Hz, Ar--H), 7.23 (1H, s, Ar--H),7.24-7.36 (6H, m, Ar--H), 7.44 (1H, s, Ar--H), 10.93 (1H, s, NH).

EXAMPLE 8(3R)-3-[N-(S)-α-Methylbenzyl-N-methyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine.3.0 Hydrogen Oxalate. Hemihydrate

a) (3S)-N-tert-Butyloxycarbonyl-3-[N-(S)-α-methylbenzyl]aminomethylPyrrolidine

Prepared from(3S)-N-tert-butyloxycarbonyl-3-methylsulphonyloxymethylpyrrolidine and(S)-α-methylbenzylamine using the procedure described for Intermediate 5part a, 6 (250 MHz, CDCl₃) 1.34 (3H, d, J=6.5Hz, Me), 1.44 (9H, s,OC(Me)₃), 1.44-2.60 (5H, m, 2 of CH₂ and CH), 2.90-3.54 (4H, m, 2 ofCH₂), 3.74 (1H, q, J=6.5Hz, CH--Me), 7.18-7.36 (5H, m, Ar--H).

b)(3R)-N-tert-Butyloxycarbonyl-3-[N-(S)-α-methylbenzyl-N-methyl]aminomethylpyrrolidine

Glacial acetic acid (0.90 ml, 15.7 mmol) and sodium cyanoborohydride(0.495 g, 7.88 mmol) were added successively to a stirred solution ofthe preceding α-(methyl)benzylaminomethylpyrrolidine (1.92 g, 6.31 mmol)in anhydrous methanol (150 ml) at 0° C. A solution of formaldehyde(0.623 g, of a 38% w/v solution, 7.88 mmol) in methanol (50 ml) was thenadded, dropwise. The mixture was stirred at 0° C. for 4.5 h and then atroom temperature for 1.25 h. Saturated K₂ CO₃ solution (25 ml) was addedand the precipitated inorganics were removed by filtration beforeremoving the solvent in vacuo. The resultant residue was taken up intoethyl acetate and washed with water (×1) and brine (×2), and dried(MgSO₄). The crude product remaining, after evaporating the solvent invacuo, was chromatoraphed on silica gel eluting with CH₂ Cl₂ /MeOH(97.5:2.5) to give the title product (2.02 g, 100%), δ (250 MHz, CDCl₃)1.34 (3H, d, J=6.7Hz, Me), 1.44 (9H, s, OC(Me)₃), 1.60-1.68 (1H, m, CHof CH₂), 1.86-1.98 (1H, m, CH of CH₂), 2.19 (3H, s, Me), 2.19-2.42 (3H,m,CH and CH₂), 2.80-3.60 (5H, m, CH and 2 of CH₂), 7.18-7.32 (5H, m,Ar--H).

c) (3R)-N(H)-3-[N-(S)-α-Methylbenzyl-N-methyl]aminomethyl Pyrrolidine

Prepared from the preceding N-Boc pyrrolidine using the proceduredescribed for Intermediate 1, part d, δ (250 MHz, CDCl₃) 1.34 (3H, d,J=6.8Hz, Me), 1.52-1.67 (1H, m, CH of CH₂), 1.94-2.08 (1H, m, CH ofCH₂), 2.17 (3H, s, Me), 2.20-2.52 (3H, m, CH and CH₂), 2.72 (1H, dd,J=7.3 and 11.3Hz, CH of CH₂), 3.07-3.13 (2H, m, CH₂), 3.25 (1H, dd,J=7.3 and 11.3Hz, CH of CH₂), 3.57 (1H, q, J=6.8Hz, CH--Me), 7.19-7.34(5H, m, Ar--H).

d)(3R)-3-[N-(S)-α-Methylbenzyl-N-methyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine.3.0 Hydrogen Oxalate. Hemihydrate.

Triethylamine (0.182 ml, 1.3 mmol) was added dropwise to a stirredsolution of(S)-2-[5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl]ethyl alcohol(0.20 g, 0.77 mmol), in anhydrous THF (12 ml). The solution was cooledto 0° C. and methane sulphonyl chloride (0.095 ml, 1.2 mmol) addeddropwise. The mixture was warmed to room temperature and stirred for 1 hbefore filtering and evaporating the filtrate in vacuo. The residue wastaken up into dichloromethane (50 ml), washed with water (×2) and dried(MgSO₄). The solvent was removed in vacuo to give the desired mesylate(0.305 g) which was used without further purification. Potassiumcarbonate (0.159 g, 1.15 mmol) and sodium iodide (0.115 g, 0.767 mmol)were added successively to a stirred solution of the preceding mesylate(0.305 g, 0.90 mmol) in anhydrous DMF (20 ml). A solution of(3R)-N-(H)-3-[N-(S)-α-methylbenzyl-N-methyl]aminomethylpyrrolidine(0.286 g, 1.31 mmol), in DMF (5 ml), was then added and the mixtureheated at 70° C. for 18 h. The reaction mixture was cooled to roomtemperature and then poured into ethyl acetate (200 ml) and washed withwater (×6). The organic layer was dried (MgSO₄) and evaporated in vacuoto give the crude product which was chromatographed on silica geleluting with CH₂ CO₂ /MeOH/NH₃ (70:8:1) to give the title-indole (59mg,14%). The 3.0 hydrogen oxalate hemihydrate salt was prepared, mp 85-90°C. (Hygroscopic), (Found: C, 55.26; H, 5.98; N, 7.60. C₂₈ H₃₆ N₄ O₂. 3.0(C₂ H₂ O₄). 0.5 H₂ O requires C, 55.21; H, 5.86; N, 7.57%), m/e461(M+1)⁺, δ (360 MHz, D₆ -DMSO) 1.41 (3H, d, J=6.8Hz, Me), 1.58-1.70 (1H,m, CH of CH₂), 2.07-2.20 (1H, m, CH of CH₂), 2.27 (3H, s, Me), 2.50-4.24(17H, m, 3 of CH and 7 of CH₂), 6.98 (1H, d, J=8.4Hz, Ar--H), 7.21 (1H,s, Ar--H), 7.26-7.44 (7H, m, Ar--H), 7.80 (1H, s, Ar--H), 10.90 (1H, s,NH).

EXAMPLE 9(3R)-3-[N-(S)-α-Methylbenzyl-N-methyl]aminomethyl-(S)-1-[2-(5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine.2.5 Hydrogen Oxalate. Monohydrate

Prepared from(S)-2-[5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl]ethylalcohol (Intermediate 6) and(3R)-N(H)-3-[N-(S)-α-methylbenzyl-N-methyl]aminomethylpyrrolidine usingthe procedure described for Example 8. The 2.5 hydrogen oxalatemonohydrate salt was prepared, low melting point (hygroscopic), (Found:C, 57.01; H, 6.38; N, 7.73. C₂₉ H₃₉ N₄ O₂. 2.5(C₂ H₂ O₄). 1.0H₂ Orequires C, 56.90; H, 6.32; N, 7.81%), m/e 475 (M+1)⁺, δ (360 MHz, D₆-DMSO) 1.42 (3H, d, J=6.8Hz, Me), 1.60-1.74 (1H, m, CH of CH₂),2.06-2.20 (1H, m, CH of CH₂), 2.27 (3H, s, Me), 2.40-4.20 (17H, m, 3 ofCH and 7 of CH₂), 2.84 (3H, s, Me), 7.00 (1H, d, J=8.4Hz, Ar--H), 7.23(1H, s, Ar--H), 7.32 (1H, d, J=8.4Hz, Ar--H), 7.34-7.40 (5H, m, Ar--H),7.44 (1H, s, Ar--H), 10.94 (1H, s, NH).

EXAMPLE 10(3S)-3-[N-(4-Fluorobenzyl)-N-methyl]aminomethyl-(S)-1-[2-(5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine.1.65 Hydrogen Oxalate. 0.6 Hydrate

The title-compound was prepared from(S)-2-[5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl]ethylalcohol and (3S)-3-[N-(4-fluorobenzyl)-N-methyl]aminomethylpyrrolidineusing the procedure described for Example 8. The 1.65 hydrogen oxalate0.6 hydrate salt was prepared, mp 88-89° C., (Found: C, 58.71; H, 6.56;N, 8.82. C₂₈ H₃₅ N₄ O₂ F. 1.65(C₂ H₂ O₄). 0.6H₂ O requires C, 58.93; H,6.24; N, 8.78%), m/e 479 (M+1)⁺, δ (360 MHz, D₆ -DMSO) 1.56-1.68 (1H, m,CH of CH₂), 2.04-2.20 (4H, m, Me and CH of CH₂), 2.40-4.18 (18H, m, 2 ofCH and 8 of CH₂), 2.82 (3H, s, Me), 6.99 (1H, d, J=8.3Hz, Ar--H),7.12-7.36 (6H, m, Ar--H), 7.43 (1H, s, Ar--H), 10.92 (1H, s, NH).

What is claimed is:
 1. A compound of formula I, or a salt or prodrug thereof: ##STR21## wherein Z represents hydrogen, halogen, cyano, nitro, trifluoromethyl, --OR⁵, --OCOR⁵, --OCONR⁵ R⁶, --OCH₂ CN, --OCH₂ CONR⁵ R⁶, --SR⁵, --SOR⁵, --SO₂ R⁵, --SO₂ NR⁵ R⁶, --NR⁵ R⁶, --NR⁵ COR⁶, --NR⁵ CO₂ R⁶, --NR⁵ SO₂ R⁶, --COR⁵, --CO₂ R⁵, --CONR⁵ R⁶, or a group of formula (a), (b), (c) or (d): ##STR22## in which the asterisk * denotes a chiral centre; X represents oxygen, sulphur, --NH-- or methylene;Y represents oxygen or sulphur; E represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms; Q represents a straight or branched alkylene chain containing from 1 to 4 carbon atoms, optionally substituted in any position by a hydroxy group; U represents nitrogen or C--R² ; V represents oxygen, sulphur or N--R³ ; R², R³ and R⁴ independently represent hydrogen or C₁₋₆ alkyl; R⁵ and R⁶ independently represent hydrogen, C₁₋₆ alkyl, trifluoromethyl, phenyl, methylphenyl, or an optionally substituted aryl(C₁₋₆)alkyl or heteroaryl(C₁₋₆)alkyl group; or R⁵ and R⁶, when linked through a nitrogen atom, together represent the residue of an optionally substituted azetidine, pyrrolidine, piperidine, morpholine or piperazine ring; M represents the residue of an azetidine, pyrrolidine or piperidine ring; R represents a group of formula --W--R¹ ; W represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms; R¹ represents --OR^(x), --SR^(x) or --NR^(x) R^(y) ; R^(x) and R^(y) independently represent hydrogen, hydrocarbon or a heterocyclic group, or R^(x) and R^(y) together represent a C₂₋₆ alkylene group; and R^(a) represents hydrogen, hydroxy, hydrocarbon or a heterocyclic group.
 2. A compound as claimed in claim 1 wherein Z represents --SO₂ NR⁵ R⁶ in which R⁵ and R⁶ are as defined in claim
 1. 3. A compound as claimed in claim 1 wherein Z represents a group of formula (b) as defined in claim
 1. 4. A compound as claimed in claim 1 represented by formula IIA, and salts and prodrugs thereof: ##STR23## wherein m is zero, 1, 2 or 3;n is 2, 3 or 4; p is zero, 1 or 2; R⁵ and R⁶ are as defined in claim 1; W¹ represents oxygen, sulphur or N--R¹² ; and R¹¹ and R¹² independently represent hydrogen, C₁₋₆ alkyl, aryl, aryl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substituted.
 5. A compound as claimed in claim 1 represented by formula IIB, and salts and prodrugs thereof: ##STR24## wherein the asterisk * denotes a chiral centre; R⁴ and Y are as defined in claim 1; andm is zero, 1, 2or 3; n is 2, 3 or 4; p is zero, 1 or 2; R⁵ and R⁶ are as defined in claim 1; W¹ represents oxygen, sulphur or N--R¹² ; and R¹¹ represents hydrogen, C₁₋₆ alkyl, aryl, aryl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substituted.
 6. A compound as claimed in claim 1 represented by formula IIC, and salts and prodrugs thereof: ##STR25## wherein the asterisk * denotes a chiral centre; R⁴ and Y are as defined in claim 1; andm is zero, 1, 2 or3; n is 2, 3 or 4; p is zero, 1 or 2; R⁵ and R⁶ are as defined in claim 1; W¹ represents oxygen, sulphur or N--R¹² ; and R¹¹ represents hydrogen, C₁₋₆ alkyl, aryl, aryl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substituted.
 7. A compound selected from:(3S)-3-(N-benzyl)aminomethyl-1-[2-(5-(N-methyl)-aminosulphonylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine; (3S)-3-(N-benzyl)aminomethyl-1-[2-(5-(aminosulphonylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;and salts and prodrugs thereof.
 8. A compound selected from:(3S)-3-(N-benzyl)aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine; (3S)-3-[N-(R)-α-(hydroxymethyl)benzyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine; (3S)-3-[N-(S)-α-methylbenzyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine; 4-[N-(R)-α-(hydroxymethyl)benzyl]amino-(S)-1-[3-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)propyl]piperidine;and salts and prodrugs thereof.
 9. A compound selected from:(3S)-3-(N-benzyl-N-methyl)aminomethyl-(S)-1-[2-(5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine; (3R)-3-[N-(S)-α-methylbenzyl-N-methyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine; (3R)-3-[N-(S)-α-methylbenzyl-N-methyl]aminomethyl-(S)-1-[2-(5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine; (3S)-3-[N-(4-fluorobenzyl)-N-methyl]aminomethyl-(S)-1-[2-(5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;and salts and prodrugs thereof.
 10. A pharmaceutical composition comprising a compound as claimed in claim 1 in association with a pharmaceutically acceptable carrier.
 11. A process for the preparation of a compound as claimed in claim 1, which comprises;(A) reacting a compound of formula III: ##STR26## wherein Z and E are as defined in claim 1; with a compound of formula IV, or a carbonyl-protected form thereof: ##STR27## wherein R², Q, M, R and R^(a) are as defined in claim 1; followed, where required, by N-alkylation by standard methods to introduce the moiety R³ ; or (B) reacting a compound of formula VII: ##STR28## wherein M, R and R^(a) are as defined in claim 1; with a compound of formula VIII: ##STR29## wherein Z, E, Q, U and V are as defined in claim 1, and L² represents a suitable leaving group; or (C) cyclising a compound of formula X: ##STR30## wherein Z, E, Q, M, R and R^(a) are as defined in claim 1, and D¹ represents a readily displaceable group; followed, where required, by N-alkylation by standard methods to introduce the moiety R³ ; or (D) cyclising a compound of formula XIII: ##STR31## wherein Z, E, Q, R², M, R and R^(a) are as defined in claim 1, and V¹ represents oxygen or sulphur; and (E) subsequently, where required, converting a compound of formula I initially obtained into a further compound of formula I by conventional methods.
 12. A method for the treatment of clinical conditions for which a subtype-selective agonist of 5-HT_(1D) receptors is indicated, which method comprises administering to a patient in need of such treatment an effective amount of a compound as claimed in claim
 1. 